Project Summary/Abstract Our goal is to provide investigators a unique rat model system and bioanylates to explore the mechanistic basis of complex diseases. The strong link between low exercise capacity and increased morbidity and mortality suggests that: aerobic energy metabolism is a central mechanistic determinant of the divide between disease and health (Aerobic Hypothesis). As an unbiased test of this hypothesis we applied divergent artificial selection for intrinsic low and high endurance treadmill running capacity starting with a founder population of genetically heterogeneous rats (N/NIH). Selection across 35 generations produced lines of low capacity runners (LCR) and high capacity runners (HCR) that differ by ~8-fold in running capacity. As predicted by the Aerobic Hypothesis, disease risks segregated strongly with low aerobic capacity. The LCR score high on many risks including reduced longevity, metabolic syndrome, and Alzheimer?s degeneration. The HCR score high for health factors such as VO2max and resistance to obesity. The LCR-HCR models fulfill the criteria for a P40 grant: A) The rats are valuable for biomedical research, but not generally available. B) There is a demonstrated need as evidenced by >400 publishing investigators, at >60 institutions, and 100 published papers. C) This resource serves the needs of multiple NIH ICs. D) The models and bioanalytes (e.g., DNA and tissues) will be made available widely. E) A high probability plan will move the resource to 100% self-sufficiency. F) A 7-part plan is established to attract high quality users. G) An advisory board will direct improvement. H) Embryo cryopreservation will serve as applied research to improve the resource. G) The resource opens new lines of investigation for understanding disease. Specific Aim 1. Continue selection of the LCR and HCR for generations 36-45 as a source of rats for users and to accumulate more recombination events that will enhance genetic mapping resolution. Specific Aim 2. Systematically establish bioanylate and electronic data resources and make these readily available. Specific Aim 3. Attract users for hypothesis-driven mechanistic study of complex diseases. As examples, we summarize three NIH funded ongoing studies: a) genotype-tophenotype analysis, b) hepatic steatosis, and c) postoperative cognitive decline. Apparently disparate conditions segregated with selection for aerobic capacity suggesting we may discover new mechanistic commonalities underlying complex diseases.